Nonalcoholic fatty liver disease (NAFLD), which is the most common liver disease in developed countries or regions, means that excess fat accumulates in the liver in a form of triglycerides (steatosis <5% of hepatocyte tissue). In addition to excess fact, patients suffering from NAFLD may be accompanied with hepatocyte injury and inflammation (fatty liver hepatitis), of which the latter is NASH (Nonalcoholic steatohepatitis). NAFLD having steatosis alone does not correlate with increased short-term morbidity or mortality, but once developed into NASH, it would increase significantly the risk of having liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Liver cirrhosis caused by NASH is one cause leading to increasing liver transplantation. In NASH patients, the morbidity and mortality caused by liver diseases are substantially increased, and NASH is closely related to increased morbidity and mortality for cardiovascular diseases. It showed by the diagnosis of asymptomatic middle-aged male patients that 46% of patients were nonalcoholic fatty liver disease (NAFLD), and 12.2% were NASH. Most patients with NAFLD are males, old people, hypertensives and diabetics. 60-76% of diabetics have NAFLD, and 22% have NASH. The number of children with NAFLD is also growing year by year, and 38-53% of obese children have NAFLD. In China, the incidence of nonalcoholic fatty liver disease has been ranked first.
At present, there is no FDA-approved medicament for the treatment of such disease. In China, clinical therapy commonly employs liver protection medicaments such as polyene phosphatidylcholine, silymarin, ursodeoxycholic acid, glycyrrhizic acid and the like.
Peroxisome proliferator-activated receptors (PPARs), which are members of the nuclear hormone receptor superfamily, are ligand-activated transcription factors that regulate gene expression. PPARs mainly comprise three subtypes: PPAP Alpha, which is mainly expressed in brown adipose tissue, liver, heart and skeletal muscle, and plays a major role in the metabolism of bile acids, lipids and sugars; PPAP Delta, which has no obvious specific expression, and may have anti-inflammatory effect; and PPAP Gamma, which has certain effects on insulin resistance. This receptor is associated with various diseases, including dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin diseases, respiratory diseases, eye disorders, IBD (irritable bowel disease), ulcerative colitis, and Crohn's disease. Since PPAR has various mechanisms beneficial to liver functions, PPAR agonists are one of the most effective potential medicaments for the treatment of fatty liver.
The following compounds are PPAR agonist compounds which have been reported in literatures.
